[Drug-induced interstitial pneumonitis due to avelumab: A case report]. / Pneumopathie interstitielle médicamenteuse à l'avelumab : à propos d'un cas.

INTRODUCTION: The anti programmed death-1 (PD-1) and the programmed death ligand 1 (PD-L1) antibodies are used as immunotherapies in the treatment of many solid tumours. Cases of interstitial pneumonitis induced by anti PD-1 have been widely described, but there are fewer data with anti PD-L1. Avelumab is a new immunotherapy of the anti PD-L1 class. CASE REPORT: A 66-year-old woman, ex-smoker, had been treated with avelumab and axitinib since November 2016 for renal cell cancer. Interstitial pneumonitis was discovered accidentally 4 months after the beginning of the treatment, with ground glass opacities, intra-lobular crosslinking and adenopathy of the 4R zone on the CT scan. An exhaustive assessment did not reveal any respiratory function defect or an infectious or immunological cause. The radiological abnormalities regressed spontaneously after cessation of treatment confirming the diagnosis of drug-induced pneumonitis. CONCLUSION: Avelumab can induce interstitial lung disease. The mechanism is uncertain and requires further studies. Monitoring of respiratory function and CT scanning are necessary for its early management.

Expression of cyclooxygenase-2 in endometrial adenocarcinoma.

Studies have shown that COX-2 is up-regulated in several epithelial carcinomas. In this study, we wish to elucidate if endometrial cyclooxygenase-2 (COX-2) expression in endometrial adenocarcinoma is increased relative to normal endometrium. Thirty-six deparaffinized tissue sections from patients with endometrial adenocarcinoma were analyzed by immunohistochemistry for the presence of COX-2. A control group consisted of 13 age-matched patients without malignancy, who underwent surgery for uterine prolapse. Statistical analysis was performed using the Kruskal-Wallis test; differences between groups were evaluated using the Fisher's Exact Test. We found that COX-2 expression was markedly increased in 13 of 36 patients (36.1%) with endometrial adenocarcinoma: in contrast only one of 13 (7.7%) control patients demonstrated increased COX-2 expression (p < or = 0.05). Eight of the 13 COX-2 positive patients in the study had well differentiated adenocarcinoma; the remaining five COX-2 positive patients had moderately and poorly differentiated adenocarcinoma (4 and 1, respectively). In conclusion, COX-2 expression in the endometrium is associated with endometrial adenocarcinoma, especially of the well differentiated type. This may provide an avenue for chemoprevention of endometrial adenocarcinoma. In addition, with new selective inhibitory drugs being developed, inhibition of COX-2 may play an adjunctive role approach to standard therapy, especially for well-differentiated endometrial carcinoma. Further studies are required to investigate the role of COX-2 expression in carcinogenesis.

Pre-prandial vs. post-prandial capillary glucose measurements as targets for repaglinide dose titration in people with diet-treated or metformin-treated Type 2 diabetes: a randomized controlled clinical trial.

OBJECTIVE: Repaglinide is an oral anti-diabetic agent that has a short duration of action, and is suitable for preventing post-prandial rises in glucose levels. Targeting post-prandial glucose levels may lead to lower HbA(1c) levels and rates of hypoglycaemia than targeting pre-prandial glucose levels. RESEARCH DESIGN AND METHODS: In 42 centres, 193 drug-naive (n = 122) or metformin-treated (n = 71) individuals with Type 2 diabetes were randomly allocated to a 40-day period of repaglinide dose-titration (starting at 0.5 mg three times daily) based on either self-measured pre-prandial or post-prandial glucose levels. They were followed for a further 12 weeks and HbA(1c) and hypoglycaemia rates were recorded. RESULTS: Repaglinide reduced HbA(1c) by 1.25 and 1.07% in the post-prandial and pre-prandial groups, respectively (P for difference = 0.6), and achieved target glucose levels in 80.7 and 66.7%, respectively (P = 0.16). The effect of titration strategy differed by baseline drug therapy, and was more effective in the metformin-treated individuals who experienced a HbA(1c) fall of 0.6 vs. 1.10% with pre-prandial vs. post-prandial titration (P for metformin-allocated group interaction = 0.043). The rate of hypoglycaemia did not differ by group. CONCLUSIONS: In drug-naive individuals with Type 2 diabetes, similar HbA(1c) levels are achieved with repaglinide when dosing is adjusted according to either post-prandial or pre-prandial levels. Conversely, in metformin-treated individuals, repaglinide dosing according to post-prandial levels may lead to better glycaemic control than dosing according to pre-prandial levels.

Wegener's granulomatosis presenting as subglottic stenosis.

Wegener's granulomatosis is an uncommon disease process that causes necrotizing vasculitis predominantly in the lungs, kidneys, and upper air-ways. Subglottic stenosis has been observed in up to 20% of patients with established diagnosis of Wegener's granulomatosis, but it is rarely the initial manifestation of the disease. This case report presents a patient with Wegener's granulomatosis who had subglottic stenosis as predominant initial manifestation, without signs of lung or kidney involvement. The diagnosis was unclear initially due to the absence of damage to these organs and to the nonspecificity of the initial biopsy findings. After stabilizing the patient, an elevated cytoplasmic pattern of antineutrophil cytoplasmic antibodies titer was obtained, which played an important role in the diagnostic process and led to a second biopsy that showed vasculitis. The patient had an excellent response to prednisone, methotrexate, and trimethoprim/sulfamethoxazole, but as with many such cases, she also required tracheo-laryngoplasty.

Effects of meal carbohydrate content on insulin requirements in type 1 diabetic patients treated intensively with the basal-bolus (ultralente-regular) insulin regimen.

OBJECTIVE: In this study, we evaluated the effects of high-(55%) and low-(40%) carbohydrate diets on insulin requirements in nine type 1 diabetic subjects treated intensively with ultralente as basal insulin and regular insulin as premeal insulin adjusted to the carbohydrate content of meals. RESEARCH DESIGN AND METHODS: Nine subjects were randomized in a crossover design to follow two diets consecutively for a period of 14 days each. A 3-day food diary was completed for each diet with the amount of carbohydrate in the mixed meals ranging from 21 to 188 g. Preprandial (5.9 vs. 6.1 mmol/l) and postprandial (8 vs. 8.9 mmol/l) capillary glucose and fructosamine (310 vs. 316 mumol/l) were comparable on both the low- and high-carbohydrate diets. RESULTS: The assessment of meal carbohydrate content by the patients was excellent, with > 85% of cases falling within 15% of computer-assisted evaluation. When premeal regular insulin was prescribed in U/10 g of carbohydrate, the postprandial glycemic rise remained constant (2.4 +/- 2.8 mmol/l) over a wide range of carbohydrate ingested (21-188 g) and was not affected by the glycemic index, fiber, and caloric and lipidic content of the meals. This tight control was maintained during the low- and high-carbohydrate diet without any change in insulin requirements (breakfast, 1.5 vs. 1.5 U/10 g of carbohydrate; lunch, 1.0 vs. 1.0; supper, 1.1 vs. 1.2) and in basal ultralente insulin requirements (22.5 vs. 21.4 U/day). CONCLUSIONS: These results indicate that in type 1 diabetic subjects 1) increasing the amount of carbohydrate intake does not influence glycemic control if premeal regular insulin is adjusted to the carbohydrate content of the meals; 2) algorithms based on U/10 g of carbohydrate are effective and safe, whatever the amount of carbohydrate in the meal; 3) the glycemic index, fiber, and lipidic and caloric content of the meals do not affect premeal regular insulin requirements; 4) wide variations in carbohydrate intake do not modify basal (ultralente) insulin requirements; and, finally 5) the ultralente-regular insulin regimen allows dissection between basal and prandial insulin requirements, so that each can be adjusted accurately and independently.

Presentation skills for the reluctant speaker.

Presentation skills are vital to clinical systems managers. This article covers four steps to successful presentations: 1) tailoring for an audience, 2) organizing a presentation, 3) mastering presentation techniques, and 4) creating effective visual aids. Tailoring for the audience entails learning about the audience and matching the presentation to their knowledge, educational level, and interests. Techniques to curry favor with an audience include: establishing common ground, relating through universal experiences, and pushing "hot buttons." Tasks involved in organizing the presentation for maximum audience interest begin with arranging the key points in a transparent organizational scheme. Audience attention is sustained using "hooks," such as graphics, anecdotes, humor, and quotations. Basic presentation techniques include appropriate rehearsal, effective eye contact with an audience, and anxiety-reducing strategies. Visual aids include flip charts, slides, transparencies, and computer presentations. Criteria for selecting the type of visual aids are delineated based on audience size and type of presentation, along with respective advantages and disadvantages. The golden rule for presentations is "Never show a slide for which you have to apologize." Rules to maximize visibility and effectiveness, including use of standard templates, sans serif fonts, dark backgrounds with light letters, mixed cases, and effective graphics, ensure that slides or projected computer images are clear and professional. Taken together, these strategies will enhance the delivery of the presentation and decrease the speaker's anxiety.

Direct activation of K(Ca) channel in airway smooth muscle by nitric oxide: involvement of a nitrothiosylation mechanism?

Clinically, nitric oxide (NO*) is widely used as a pulmonary vaso- and bronchodilator agent. However, the precise molecular mechanisms by which NO. induces smooth muscle relaxation are not well established. It has been suggested that NO. relaxes airway smooth muscle (ASM) via a 3',5'-cyclic guanosine monophosphate (cGMP)-dependent pathway, and our previous work has shown that Ca2+-activated K+ (KCa) channels are susceptible to cGMP-dependent protein kinase (PKG)-dependent phosphorylation (A. Alioua, J. P. Huggins, and E. Rousseau. Am. J. Physiol. 1995;268:L1057-L1063). To assess whether KCa channels are also directly activated by NO. or one of its derivatives such as peroxynitrite, the activity of these channels was measured upon fusion of sarcolemmal vesicles derived from bovine tracheal smooth muscle cells into planar lipid bilayers (PLB). It was found that in the absence of adenosine triphosphate (ATP), cGMP, and cGMP-dependent protein kinase, NO* donors such as 1-propanamine-3-(2-hydroxy-2-nitroso-1-propylhydrazine) (PAPA NONOate) or 3-morpholinosydnonimine hydrochloride (SIN-1) in the presence of superoxide dismutase (SOD), added on either side of the bilayer, caused a concentration- dependent increase in the open probability (Po) of KCa channels without altering their unitary conductance. Release of NO*, which was measured by chemiluminescence analysis in parallel experiments, affected the gating behavior of KCa channels in the presence of SOD and ethyleneglycol-bis-(beta-aminoethyl ether)- N,N'-tetraacetic acid (EGTA) by reducing the mean closed times and increasing the number and duration of short open events. PAPA NONOate, a true NO. donor, had similar effects in the presence of ethylenediaminetetraacetic acid (EDTA), a heavy-metal chelator, and K-urate, a peroxynitrite scavenger. Addition of either 5 mM dithiothreitol (DTT) or 5 mM reduced glutathione (GSH), as well as 5 mM N-ethylmaleimide (NEM)-an alkylating agent-to the trans (intracellular) side of an experimental chamber slightly increased channel Po but prevented further channel activation by NO* donors. However, neither DTT nor GSH was able to reverse the effect of NO*. In contrast to SIN-1, DTT had no effect when added to the cis (extracellular) side of the chamber. This suggests that the effect of NO* is most likely due to a chemical modification (nitrothiosylation) of intracellular sulfhydryl group(s). Neither PAPA NONOate (NO*), nor SIN-1 had any effect on sarcolemmal Cl- channels reconstituted from the same membrane preparations. Pharmacomechanical measurements made on epithelium-denuded rat bronchus showed that 100 nM charybdotoxin decreased the sensitivity of bronchial smooth muscle to SIN-1-induced relaxations. Altogether, our data suggest that NO-induced bronchorelaxation occurs partly via a direct activation of KCa channels, possibly through a covalent interaction with the cytoplasmic side of their alpha subunit.

Fluoxetine improves insulin sensitivity in obese patients with non-insulin-dependent diabetes mellitus independently of weight loss.

OBJECTIVE: To study the effect of fluoxetine, a specific serotonin reuptake inhibitor, on insulin sensitivity in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) independently of its action on body weight. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled trial, insulin-mediated glucose disposal was measured in 12 obese patients with NIDDM on diet alone before and after four weeks of treatment with either placebo (n = 6) or fluoxetine (n = 6) at a dose level of 60 mg once a day. Insulin-mediated glucose disposal was assessed by the 2-step euglycemic hyperinsulinemic clamp technique. Patients were instructed on a weight-maintaining diet. RESULTS: Insulin infusion at 40 mU.m-2.min-1 resulted in insulin levels of 720 +/- 70 pmol. L-1 with a mean plasma glucose value of 6.4 +/- 0.2 mmol. L-1. Compared to placebo, fluoxetine increased glucose disposal (M) by 2.4-fold (P < 0.05), the insulin sensitivity index (M/I) by 2.7-fold (P < 0.03) and the glucose metabolic clearance rate (MCR) by 2.9-fold (P < 0.03). Insulin infusion at 400 mU.m-2. min-1 elicited insulin levels of 12947 +/- 1512 pmol. L-1 with a mean plasma glucose value of 5.6 +/- 0.4 mmol. L-1. Compared to placebo, fluoxetine increased M by 30% (P = NS), M/I by 40% (P < 0.04) and MCR by 23% (P < 0.04). Patient weight remained stable throughout the study with no change in dietary intake. CONCLUSION: Fluoxetine improves insulin-mediated glucose disposal in obese patients with NIDDM independently of weight loss.

Resumes and cover letters: a guide.

Many beginning managers have poorly constructed resumes. The content of resumes is fairly standard. The style should be clear and concise. Common pitfalls include irrelevant material, distracting detail, and repetition. The cover letter is a more flexible document that introduces the resume. Like the resume, the cover letter should cover some essential details clearly and concisely. Additionally, the cover letter should detail important qualifications and can elaborate on specific aspects of your resume. The cover letter should be tailored to fit the opening.

Inhibition of 1,25(OH)2D production by hypercalcemia in osteitis fibrosa cystica: influence on parathyroid hormone secretion and hungry bone disease.

Primary hyperparathyroidism is usually associated with normal or elevated serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels. We report a 63-year-old patient with extreme hypercalcemia (ionized serum calcium, 2.51 mmol/l; normal range, 1.19-1.36), very high serum concentrations of intact immunoreactive parathyroid hormone (iPTH) (145 pmol/l; normal range, 1-6.8), radiological lesions of osteitis fibrosa cystica, only mildly impaired renal function (creatinine clearance, 69 ml/min/m2) and very low serum levels of 1,25(OH)2D (28.8 pmol/l; normal range, 72-120). Presurgery normalization of the calcemia with normal saline, salmon calcitonin and pamidronate caused an increase in 1,25(OH)2D serum concentration to 228.3 pmol/l. A negative correlation could be established between ionized calcium and 1,25(OH)2D levels during that period (r2 = 0.80, P < 0.04). While serum calcium decreased with treatment, serum iPTH also decreased to 48.6 pmol/l, suggesting some 1,25(OH)2D inhibition of parathyroid adenoma function. Serum alkaline phosphatase also rose from 309 to 390 units/l (normal range, 25-97), suggesting the beginning of resolution of her osteitis fibrosa cystica prior to surgery. Surgical removal of a parathyroid adenoma was associated with a decrease in serum calcium and iPTH levels. To our surprise, the hypocalcemia could be managed easily with 1500 mg of oral calcium carbonate daily, even if the hungry bone disease became more active with an increase in alkaline phosphatase to 486 units/l. This was explained by the very high levels of serum 1,25(OH)2D (> 200 pmol/l) which prevailed in the postsurgery period and were probably related to decreased bone resorption and increased bone formation. This case illustrates that normalizing serum calcium prior to surgery in patients with primary hyperparathyroidism and osteitis fibrosa cystica can be highly beneficial.

Gamma delta T cells in human decidua.

OBJECTIVE: Our purpose was to assess the presence and frequency of gamma delta T cells in the decidua of term and first-trimester pregnancies. STUDY DESIGN: Term and first-trimester placentas were obtained from normal subjects. Frozen sections and cell suspensions were prepared from decidual tissue and stained with monoclonal antibodies to T cell markers. Cell sorter analysis was performed. RESULTS: gamma delta T cells in term decidual cell preparations were enriched 2.4-fold compared with peripheral blood. Immunohistochemical staining of term decidual tissue demonstrated many gamma delta + and CD3+ T cells, fewer CD8+ cells, and rare CD4+ cells. In contrast, first-trimester decidua was found to be devoid of gamma delta + T cells, by both cell sorter analysis and immunohistochemical methods. CONCLUSIONS: Term, but not early, decidua harbors a resident T-cell population that is significantly enriched in gamma delta T cells compared with blood. These lymphocytes may provide an added defense mechanism against infection during the peripartum.

Gastric inhibitory polypeptide-dependent cortisol hypersecretion--a new cause of Cushing's syndrome.

BACKGROUND: Corticotropin-independent nodular adrenal hyperplasia is a rare cause of Cushing's syndrome, and the factors responsible for the adrenal hyperplasia are not known. METHODS: We studied a 48-year-old woman with Cushing's syndrome, nodular adrenal hyperplasia, and undetectable plasma corticotropin concentrations in whom food stimulated cortisol secretion. RESULTS: Cortisol secretion had an inverse diurnal rhythm in this patient, with low-to-normal fasting plasma cortisol concentrations and elevated postprandial cortisol concentrations that could not be suppressed with dexamethasone. The cortisol concentrations increased in response to oral glucose (4-fold increase) and a lipid-rich meal (4.8-fold increase) or a protein-rich meal (2.6-fold increase), but not intravenous glucose. The infusion of somatostatin blunted the plasma cortisol response to oral glucose. Intravenous infusion of gastric inhibitory polypeptide (GIP) for one hour increased the plasma cortisol concentration in the patient but not in four normal subjects. Fasting plasma GIP concentrations in the patient were similar to those in the normal subjects; feeding the patient test meals induced increases in plasma GIP concentrations that paralleled those in plasma cortisol concentrations. Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin. In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producting or aldosterone-producing adenomas responded to corticotropin but not to GIP. CONCLUSIONS: Nodular adrenal hyperplasia and Cushing's syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder.

Hemispheric differences in visual search of simple line arrays.

The effects of perceptual organization on hemispheric visual-information processing were assessed with stimulus arrays composed of short lines arranged in columns. A visual-search task was employed in which subjects judged whether all the lines were vertical (same) or whether a single horizontal line was present (different). Stimulus-display organization was manipulated in two experiments by variation of line density, linear organization, and array size. In general, left-visual-field/right-hemisphere presentations demonstrated more rapid and accurate responses when the display was perceived as a whole. Right-visual-field/left-hemisphere superiorities were observed when the display organization coerced assessment of individual array elements because the physical qualities of the stimulus did not effect a gestalt whole. Response times increased somewhat with increases in array size, although these effects interacted with other stimulus variables. Error rates tended to follow the reaction-time patterns. The results suggest that laterality differences in visual search are governed by stimulus properties which contribute to, or inhibit, the perception of a display as a gestalt. The implications of these findings for theoretical interpretations of hemispheric specialization are discussed.